One of the important classes of cytotoxic agents is the taxanes which include paclitaxel, its derivatives and analogs. This invention relates to methods and compositions of taxane orotates that prevent or inhibit the body weight loss when taxanes are used in the treatment of cancers. Paclitaxel belongs to a class of chemotherapy drugs called plant alkaloids. The taxanes are made from the bark of the Pacific Yew tree (taxus). Paclitaxels has been approved for clinical use in the treatment of refractory ovarian cancer. It is effective for chemotherapy for several types of cancers including breast and has been approved for treatment of breast cancer as well. It is a candidate for treatment of cancers in the skin, lung cancer, head and neck cancer, bladder cancer, prostate cancer, esophageal cancer, polycystic kidney disease and malaria.
Paclitaxel is only slightly soluble in water and thus has created significant problems in developing suitable injectable and infusion formulations of paclitaxel for iv infusion using Cremophor EL™ (polyethoxylated castor oils) as drug carrier. Cremophor EL™ however, when administered intravenously, is itself toxic and prodices vasodilation, labored breathing, lethargy, hypotension and death in dogs.
To circumvent serious side effects of paclitaxel, paclitaxel is encapsulated in liposomes and microparticulate lipoidal vesicles. Paclitaxel encapsulated in cationic liposomes carries paclitaxel to blood vessels and thereby provides antiangiogenic effects. Paclitaxel encapsulated in liposomes prevented melanoma growth and invasiveness and improved survival in mice. In contrast, equimolar concentrations of paclitaxel solubilized in Cremophor EL™ had only insignificant effects on tumor growth in vivo. R. Kunstfeld et al, J. Inves Dermatol, 2003, 120:476-482.
Another formulation of paclitaxel available is Abraxane® or nab paclitaxel. It is paclitaxel bound to albumin in the form of nanoparticles. It is Cremophor EL™ free and is designed to reduce adverse reactions associate with Cremophor EL™ use. U.S. Pat. No. 5,916,596, issued Jun. 29, 1999 to Desai N P et al; U.S. Pat. No. 6,395,770, issued May 28, 2002 to Broder S et al.; U.S. Pat. No. 6,730,698, issued May, 4, 2004 to Broder S et al.; and M. Stenger, Community Oncology 2: 214-215 (2005)
Other taxanes include docetaxel (N-debenzoyl-N-tert-butoxycarbonyl-10-deacyl pactitaxel) has become commercially available as Taxotere® in parenteral form for treatment of breast cancer. The Chemotherapy Source Book, ed M. C. Perry, Lippincott Williams & Wilkins, 3rd ed. 2001.
Great hopes have centered on the use of nanoparticles that are suitable for parenteral administration in aqueous suspension. This form of delivery obviates the need for administration of substantially water insoluble pharmacological agents (e.g., paclitaxel) in an emulsion containing for example, ethanol and polyethoxylated castor oil, diluted in saline because of the disadvantage of such known compositions is their propensity to produce side effects. Instead nanoparticles are prepared by a solvent evaporation technique from an oil-in-water emulsion under conditions of high shear forces by using human serum albumin as a stabilizing agent. Nevertheless, treatment related toxicities for sensory neuropathy, neutropenia, nausea, diarrhea and anorexia persist even with nab paclitaxel.
Obesity is implicated as a risk factor in the incidence and mortality due to cancer. However, there remains little or conflicting evidence about body weight changes, and specifically body weight loss due to side effects of cytotoxic agents, because of confounding variables. However, there is some evidence that a decrease in body weight during chemotherapy could potentially impact survival of cancer patients. Clearly there is need for chemical modification of paclitaxel molecule, regardless of whatever type of formulation it is administered as, for example i) in emulsion containing for example, ethanol and polyethoxylated castor oil, diluted in saline, ii) encapsulated in liposomes and microparticulate lipoidal vesicle, or iii) Abraxane® or nab paclitaxel which is paclitaxel bound to albumin in the form of nanoparticles.
The present invention related to orotates of taxane cytotoxic agents and in particular to methods of conversion of the taxanes to their orotate compounds to prevent or inhibit their toxic side effects, including body weight loss. Body weight loss during chemotherapy has been found in ovarian cancer to be a surrogate for body reaction to the cytotoxic agent and may predict quality of life and clinical outcome (Hess, L. M. et al., Gynecol Oncol. 2007, 107(2): 260-265).
Weight Change During Chemotherapy—Change of body weight during chemotherapy was found to be a strong factor for overall survival in ovarian cancer patients. Specifically, it was found that loss of body weight during primary therapy was an indicator for poor overall survival. In other words, weight gain was an indicator for improved survival. The chemotherapeutic agents studied in the retrospective study involving 792 advanced ovarian cancer patients were platinum and paclitaxel.
However, paclitaxel is also used in the treatment of breast cancer, non-small cell and small cell lung cancer, head and neck cancer, esophageal cancer, prostate cancer, bladder cancer and AIDS-related Kaposi's sarcoma. Thus there is a great need for safer formulations of paclitaxel which give a better rate of response, a wider spectrum of response, and/or reduce weight loss during chemotherapy. In particular, orotate compounds of paclitaxel and other taxanes may provide options for using improved formulations of paclitaxel.
The present invention is distinguishable from the prior art references described above because none of the prior art addresses the issue of preventing and/or reducing the body weight loss during chemotherapy, while maintaining the antitumor activity, as a strategy to reduce the toxicity and adverse drug reactions. More effective and less toxic taxanes orotates are widely sought and are a fundamental object of the invention. The pertinent subject matter of the above references is specifically incorporated herein by reference.